The overall goal of Project 3 of the Research Program is to chemically define oxidative pathways that[unreadable] participate in the initiation and propagation of the inflammatory responses in asthma. Leukocytes play an[unreadable] essential role in the body, destroying pathogenic microorganisms and tumor cells. They also have great[unreadable] potential to harm healthy tissue. Because oxidative damage is cumulative, this potential is enhanced in[unreadable] chronic inflammatory diseases like asthma. We have used mass spectrometry to show that eosinophils and[unreadable] neutrophils, via their respective unique heme peroxidases, eosinophil peroxidase (EPO) and[unreadable] myeloperoxidase (MPO), promote protein oxidative damage in human asthmatic airways. Recent studies[unreadable] also suggest an important role for lactoperoxidase (LPO), a related member of the heme peroxidase[unreadable] superfamily, in maintenance of airway innate immune defenses.[unreadable] The present proposal is predicated upon the hypothesis that oxidative reactions, such as those mediated[unreadable] by redox-active transition metal ions, nitric oxide-derived oxidants, and mammalian heme peroxidases, affect[unreadable] acute and chronic features of the disease process, including airways remodeling. Our evidence suggests[unreadable] mechanistically distinct oxidative pathways promote structurally definable alterations to lipid and protein[unreadable] components of the bronchiole wall in asthmatic airways. We propose to integrate studies on basic[unreadable] mechanisms with a search for specific reaction products that reveal whether relevant pathways operate in[unreadable] animal models of pulmonary inflammation and in human asthma.[unreadable] We will use murine models to define specific enzymatic participants that contribute to formation of[unreadable] specific bioactive eicosanoids, protease resistant covalent cross-links, and other defined oxidative[unreadable] modifications in lung and airways following allergen challenge. With Project 2 we will explore the role of[unreadable] extracellular matrix on modulating defined oxidative processes in asthmatic airways. Through human clinical[unreadable] investigations and collaborations with Project 1 we will explore the potential clinical utility of specific[unreadable] structurally informative oxidative adducts as non-invasive markers for disease presence, severity, pulmonary[unreadable] function, and the extent of airways remodeling. All cores are extensively used by this Project. Collectively,[unreadable] the proposed studies will provide insights into oxidative processes participating in inflammatory injury and[unreadable] remodeling in asthma.